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Biomedical subjects

J Krause

Publications and source records attributed to J Krause.

At least 73 records · Page 4Linked to original sources
PubMed1991

Pharmacokinetics and hepatic catabolism of tissue-type plasminogen activator.

Recombinant tissue-type plasminogen activator (rt-PA, alteplase, Actilyse, Activase; CAS 105857-23-6) is the most effective agent currently available for thrombolytic therapy of life-threatening diseases such as acute myocardial infarction. It acts by rapid, clot-specific lysis of pathological thrombi, with only limited effects on systemic hemostasis. Pharmacokinetics of rt-PA have been extensively characterized in animal species and man, and can be generally described by a 3-compartment model. Preferred analytical methods for rt-PA in plasma are ELISA and chromogenic activity assays. The dominant plasma half-life of rt-PA in myocardial infarction patients is short (3.6 min), which allows excellent control of plasma levels during therapy. Steady-state plasma concentrations effecting coronary thrombolysis using the current dosage regimen are 2.2 micrograms/ml. A deep compartment results in elevated rt-PA concentrations several hours after termination of infusions, which may contribute to short-term maintenance of patency of reperfused blood vessels. Clearance of rt-PA can be saturated in animals at very high plasma concentrations (Km = 12-15 micrograms/ml), however, pharmacokinetics in clinical settings are linear. Clearance occurs via hepatic receptor mediated endocytosis and intracellular degradation in liver parenchymal, endothelial and Kupffer cells. The catabolism involves coated pits, coated vesicles, endosomes, and finally degradation in lysosomes. Current evidence supports the existence of hepatic receptors recognizing carbohydrate as well as polypeptide determinants in rt-PA. In conclusion, increasing knowledge of rt-PA pharmacokinetics will contribute to the optimization of new clinical dosage regimens, such as front-loaded infusions and boluses, and to the identification of novel molecular targets for pharmacologic control of rt-PA catabolism and of circulating fibrinolytic activity.

Animals↗
PubMed1991

Endocytosis of the recombinant tissue plasminogen activator alteplase by hepatic endothelial cells.

The glycoprotein tissue-type plasminogen activator (t-PA, alteplase, CAS 105857-23-6) is a serine protease consisting of 527 amino acids and can activate plasminogen to plasmin, which subsequently dissolves the fibrin network of a thrombus. This activation occurs selectively on the thrombus, making recombinant t-PA a very effective agent in the treatment of thromboembolic disorders. t-PA has a short in vivo half-life and is rapidly removed from the circulation by the liver. The catabolism of t-PA involves receptor-mediated endocytosis and intracellular degradation in several cell types of the liver namely hepatic endothelial, parenchymal and Kupffer cells. Liver endothelial cells have been reported to possess a specific uptake system for t-PA based on the recognition of the high mannose carbohydrate structures on Asn117. To further elucidate the involvement of the mannose receptor on sinusoidal endothelial cells in the hepatic catabolism of t-PA and to identify the mechanisms involved, biochemical as well as electron microscopic studies were performed. The biochemical studies revealed that the removal of the mannose side chain in t-PA significantly reduced its clearance and degradation in isolated perfused livers. The binding of t-PA to preparations of primary hepatocytes and liver cell membranes could not be competed for by various sugars and glycoproteins, and was not dependent on the presence of carbohydrates on the molecule. This ruled out a major relevance of the sugar moieties of t-PA in its recognition by liver cells that were not of endothelial origin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Different receptors mediate the hepatic catabolism of tissue-type plasminogen activator and urokinase.

Tissue-type plasminogen activator (t-PA) and urokinase (u-PA) are proteins with partial structural similarity and which are of importance in the therapy of thrombotic diseases. Both are known to be cleared from the circulation in vivo by uptake in the liver. The present study investigated whether the hepatic catabolism of u-PA and t-PA is mediated by a common receptor system. Four experimental protocols of increasing complexity were used: hepatocyte plasma membranes, isolated primary hepatocytes, liver perfusion and whole animals. For t-PA, a specific high-affinity binding site to hepatocytes and plasma membranes could be defined with a mean Kd of 4 +/- 3 nM, whereas the Kd for u-PA was less than 300 nM. Binding of t-PA could not be competed for by u-PA, and vice versa. Furthermore, clearance of t-PA in isolated perfused rat livers and in rabbits in vivo was 3-fold higher than that of u-PA, and a 50-100-fold molar excess of u-PA failed to inhibit clearance of t-PA in either system, and vice versa. Taken together, the results imply that hepatic elimination of t-PA and u-PA is mediated by distinct receptor systems of differing affinity.

Animals↗
PubMed1990

Nonlinear pharmacokinetics of tissue-type plasminogen activator in three animal species and isolated perfused rat liver.

Tissue-type plasminogen activator (t-PA) is cleared rapidly from the circulation via hepatic catabolism, but the capacity of this process is unknown. In this study, increasing doses of human t-PA were administered to rats, rabbits and marmoset monkeys, and in an isolated perfused rat liver system. t-PA concentrations in plasma and perfusate were analyzed pharmacokinetically using procedures in which nonlinear multicompartment models with Michaelis-Menten elimination were fitted to data sets from all doses simultaneously for each species. Elimination of t-PA was saturable, with Km = 12-15 micrograms/ml and Vmax = 200-350 micrograms/ml/hr in vivo. In isolated rat liver, t-PA elimination capacity was considerably reduced, with Km = 1.5 micrograms/ml and Vmax = 3.7 micrograms/ml/hr. At nonsaturating doses, plasma clearance in vivo was 18-23 ml/min/kg and the dominant half-life was 1.1-2.4 min, compared with 8 ml/min/kg and 4.4 min, respectively, in humans; rat liver perfusate clearance was 0.29 ml/min/g. It is concluded that disposition kinetics of t-PA are very similar across species, extrahepatic clearance may be significant in vivo and clearance capacity becomes limited only at plasma concentrations far in excess of clinical therapeutic values. Nonlinearity is, however, of practical significance in liver perfusion and in animal pharmacology studies utilizing high t-PA doses.

Animals↗
PubMed1990

[Disorders of neuromuscular function and respiration].

Neuromuscular disorders of varying aetiology frequently lead to respiratory failure. This situation contrasts with the rare application of suitable tests of pulmonary function in this group of patients. As a result, respiratory complications are not detected until they have progressed to a terminal stage. With the sequential measurement of vital capacity, and a determination of the maximum inspiratory and expiratory pressures (PImax and PEmax), we have reliable and practicable diagnostic measures available that permit the recognition of respiratory failure at an early stage. This fact is of particular importance, since the application of modern ventilation techniques in suitable patients can make a substantial contribution towards both improving the patient's quality of life and prolonging it.

Diaphragm↗
PubMed1990

[A computerized processing unit for ambulatory diagnosis of sleep apnea and nocturnal hypoxemia].

A new mobile device for the evaluation of the sleep-apnoea-syndrome in outpatients prior to conventional polysomnography, processes and stores the oronasal airflow detected by a thermistor, and the heart rate and oxygen saturation in a microprocessor unit. The major problem in on-line data processing of these variables is the interpretation of the thermistor signal for correct apnoea detection. This preliminary study investigates the reliability of the computer algorithm by control of the automatic airflow assessment. With a sensitivity of 97.3% the algorithm proved to be extreme reliable. Combined with the detection of heart rate and oxygen saturation it provides the capacity for comprehensive analysis of cardiorespiratory events and appears to be suitable for application in an outpatient setting.

Algorithms↗
PubMed1990

[Acute anterior wall infarct with intractable ventricular fibrillation: successful therapy by recanalization of a left anterior descending coronary artery occlusion].

A 35-year-old male patient was admitted to the intensive care unit of a community hospital with an acute anterior myocardial infarction complicated by initial recurrent episodes of ventricular fibrillation and successful resuscitation. Persistent malignant ventricular arrhythmias during the following days necessitated external defibrillation approximately 250 times. The patient was transferred to the Hannover Medical School, where the occluded left anterior descending coronary artery was successfully recanalized. Eight days later, the malignant ventricular tachyarrhythmias ceased and after 59 days of hospitalization the patient could be discharged in stable condition.

Adult↗
PubMed1989

X-ray crystallographic analysis of the structural distortions induced by substitution and annulation of the dodecahedrane nucleus.

Methyl dodecahedranecarboxylate, C22H22-O2, (4), Mr = 318.42, monoclinic, C2/c, a = 12.600 (2), b = 7.992 (4), c = 28.975 (7) A, beta = 101.79 (2) degrees, V = 2856 A3, Z = 8, Dx = 1.48 g cm-3, lambda(Mo K-alpha) = 0.71073 A, mu = 0.84 cm-1, F(000) = 1360, T = 294 K, R = 0.044 for 2109 unique reflections with Fo2 greater than 3 sigma(Fo2). 21-Phenylcyclopropadodecahedrane, C27H24, (5), Mr = 348.49, tetragonal, P4(2)/n, a = 17.528 (3), c = 10.752 (2) A, V = 3303 A3, Z = 8, Dx = 1.40 g cm-3, lambda(Mo K-alpha) = 0.71069 A, mu = 0.85 cm-1, F(000) = 1488, T = 295 K, R = 0.053 for the 1773 unique reflections with Fo2 greater than 1 sigma(Fo2). The molecular geometries of methoxycarbonyldodecahedrane (4) and 21-phenylcyclopropadodecahedrane (5) are compared to those of the parent C20H20 hydrocarbon (1) and its 1,16-dimethyl derivative (2). For both (2) and (4), the framework is modestly distorted by the substituents, the intracavity distance being more extended along the axis that contains the pendant group(s). Remarkably for (5), its cyclopropane ring has all C-C bonds and internal angles essentially equal, and those dodecahedrane bonds in the immediate vicinity of the ring fusion are extensively perturbed.

Molecular Structure↗
PubMed1989

Gastrointestinal transit and gastric acid secretion in patients with achalasia.

Previous studies suggest that patients with achalasia exhibit degenerative changes of extraesophageal nerve fibers. We investigated whether these morphological alterations are associated with functional abnormalities of the gastrointestinal tract. Patients with achalasia had a normal acid secretory response (5.5 +/- 1.5 mmol/hr) to vagal stimulation when compared to controls (6.0 +/- 5.3 mmol/hr). However, the half time of gastric emptying of liquids was significantly shorter in patients with achalasia (10.4 +/- 1.8 min) than in control subjects (19.3 +/- 11.3 min) (P less than 0.01). Although there was a tendency towards a more rapid gastrointestinal transit in patients with achalasia, these changes failed to reach statistical significance. It is concluded that patients with achalasia have a gastric emptying disorder that could either be explained by a selective defect of extraesophageal vagal inhibitory nerve fibers or as an epiphenomenon occurring as a consequence of impaired esophageal emptying.

Adolescent↗
PubMed1989

A German validation study of the inventory to diagnose depression.

The Inventory to Diagnose Depression (IDD), a self-rating scale designed to identify major depressive episodes (MDE) according to DSM-III, was validated in a sample of 83 inpatients. Depending whether the time criterion of MDE was included or omitted, 63 or 77 patients obtained a syndrome diagnosis of MDE established by means of a structured clinical interview (Polydiagnostic Interview) which served as yardstick. Sensitivity (84.1% with time criterion, 89.6% without time criterion), specificity (60%, 50%), predictive value (67.8%, 64.2%) and kappa (0.43, 0.29) were calculated and found to necessitate improvement for a reasonable application of the IDD in epidemiological and clinical settings. Adapting the IDD algorithm to DSM-III-R diagnosis of MDE, analogous results were obtained.

Adult↗
PubMed1989

Properties of molecular variants of tissue-type plasminogen activator.

Tissue-type plasminogen activator (t-PA), an important component of the fibrinolytic system, is now available as a biotechnologically manufactured recombinant protein for therapeutic use. It has proved highly effective in the clinical therapy of acute thromboembolic diseases such as myocardial infarction and pulmonary embolism. t-PA activates plasminogen to plasmin, which subsequently dissolves the fibrin network of a blood clot. This activation by t-PA occurs selectively on the clot surface, with negligible systemic side effects. The half-life of t-PA in vivo is in the order of minutes due to rapid hepatic elimination. t-PA is a glycoprotein with serine protease activity and consists of a polypeptide chain with 527 amino acids. Recently, intensive research efforts have been devoted to modification of the molecular structure of t-PA, with the objective of further increasing fibrin specificity and catalytic activity, or reducing the rate of elimination. As a result, considerable insights into structure-function relationships within the t-PA molecule have been gained, but as yet no clinically utilizable variant has been constructed which is in all respects superior to naturally occurring t-PA.

Animals↗
PubMed1989

[Surgery of pleomorphic adenoma of the parotid gland].

In literature opinion is divided, whether for treatment of pleomorphic adenoma in the parotid gland partial parotidectomy is adequate or complete parotidectomy is necessary. In a retrospective analysis of 123 complete parotidectomies in pleomorphic adenomas the macroscopic tumor extension was compared with the microscopic findings. Additionally 35 pleomorphic adenomas were examined in histological serial sections. The retrospective analysis showed in 6%, the serial sections in 11% microscopic tumor in the macroscopic tumorfree inner lobe. A clinical follow-up examination of 85 patients operated by complete parotidectomy because pleomorphic adenoma resulted in a relapse-quota of 3.5%. The function of the facial nerve was in most cases normal, in 8.2% a weakness of the mandibular branch was found. These results indicate that the risk to leave tumor can be reduced evidently by a complete parotidectomy.

Adenoma, Pleomorphic↗
PubMed1989

[A modified unit for detecting sleep apnea].

A comprehensive diagnostic work-up of patients with a suspected sleep apnea syndrome must include conventional polysomnographic monitoring during the night. On account of the considerable staff and technical requirement, however, this definitive diagnostic measure is not suitable for use as a screening programme. For this reason we undertook to develop a device for the computer-aided recording of sleep apnea. The heart of the unit is a 65816 microprocessor with an address capacity of 16 Mbytes. The oro-nasal airflow is recorded with the aid of thermistors, and, after digital filtering, the respiratory rate is continuously recorded on the basis of this signal. Continuous recording of the heart rate and oxygen saturation, is also effected, the recorded data being stored in the microprocessor. On conclusion of the data acquisition phase, evaluation and a compressed display is shown on any conventional personal computer. Our preliminary experience reveals that the algorithm employed is extremely reliable for the detection of respiration rate and apnea, even in the presence of unfavourable signal forms. Clinically relevant deviations from manual evaluation do not occur. As was to be expected, processing of the signals for heart rate and oxygen saturation presented no problems.

Humans↗
PubMed1989

[Morphologic studies of asbestos-cement surfaces].

A scanning electron microscopic procedure was used for the investigation of asbestos-cement surfaces. The samples of uncoated asbestos-cement sheets were up to 50 years old, coated asbestos-cement materials were 16 years old in maximum. Our results demonstrate that suitable coating systems effectively protect the asbestos-cement surface. On the other hand uncoated asbestos-cement shows a release of asbestos fibres locked up in cement. Therefore uncoated asbestos-cement sheets are emission sources of asbestos fibres. Wether the weathered material coursed a increase of asbestos fibre concentration in ambient air will be a subject of further investigations.

Asbestos↗
PubMed1988

Purification and characterization of the pore forming protein of yeast mitochondrial outer membrane.

One of the major outer membrane proteins of yeast mitochondria was isolated and purified. It migrated as a single band with an apparent molecular weight of 30 kDa on a SDS-electrophoretogram. When reconstituted in lipid bilayer membranes the protein formed pores with a single channel conductance of 0.45 nS in 0.1 M KCl. The pores had the characteristics of general diffusion pores with an estimated diameter of 1.7 nm. The pore of mitochondrial outer membranes of yeast shared some similarities with the pores formed by mitochondrial and bacterial porins. The pores switched to substates at voltages higher than 20 mV. The possible role of this voltage-dependence in the metabolism of mitochondria is discussed.

Intracellular Membranes↗
PubMed1988

Use of the Technicon H-1 in the characterization of leukemias.

The Technicon H-1 is a hematology analyzer that performs a complete blood cell count and white blood cell differential using both cytochemistry and flow technology. Two white blood cell cytograms are produced based on peroxidase activity and nuclear characteristics of the cells. Ninety cases of leukemia were studied. The 25 cases of acute lymphocytic leukemia (ALL) could be distinguished from the 39 cases of acute nonlymphocytic leukemia as the lymphocyte percentage was greater than 50% in the ALL cases and the mean peroxidase index value was 0 in 80% of the cases. The ALL cases and the chronic lymphocytic leukemia cases also had different cytogram patterns. Subtypes of acute nonlymphocytic leukemia could not be absolutely distinguished, although promyelocytic leukemias (M3) had characteristic cytograms and a monocyte percentage above 15% suggested a monocytic component (M4 or M5). Chronic myelogenous leukemia likewise seemed to have a recognizable pattern. Since a sample takes only 60 s to process, information is readily available. The unique data available from this instrument should provide a significant advancement in the automated hematology field.

Adolescent↗